The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL
The PI3Kδ Inhibitor Idelalisib Inhibits Homing in an in Vitro and in Vivo Model of B ALL
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DOI：
10.3390/cancers9090121
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发表时间：
2017-09-01
期刊：
影响因子：
5.2
通讯作者：
Kim, Yong-Mi
中科院分区：
文献类型：
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作者：
Adam, Etai;Kim, Hye Na;Kim, Yong-Mi
人们继续寻求有针对性的治疗方法，以减少化疗的发病率，并改善耐药白血病的反应。急性淋巴细胞白血病(ALL)细胞与骨髓基质细胞的黏附触发细胞内信号，促进细胞黏附介导的耐药(CAM-DR)。IDelalisib是美国食品和药物管理局(FDA)批准的PI3K特异性抑制剂，已被证明与利妥昔单抗联合应用在CLL中下调p-Akt和延长生存时间方面是有效的；在此，我们探讨其用于B ALL的可能性并探讨其作用机制。与OP9基质细胞接触的原代B ALL显示p-Akt升高(Ser473)。Idelalisib降低了具有不同遗传损害的ALL患者样本中的p-Akt。在测试样本的子集中，与长春新碱单一治疗相比，在长春新碱中加入艾得拉西布可抑制细胞增殖。Idelalisib在体外抑制了所有细胞向SDF-1的迁移，并在体内阻止了所有细胞向骨髓的归巢。这份报告测试了PI3K抑制剂在比之前报道的更多样化的ALL组中，这是第一个发表的关于idelalisib抑制所有细胞归巢到骨髓的报告。我们的数据支持IDelalisib治疗B ALL的进一步临床前评估。
The quest continues for targeted therapies to reduce the morbidity of chemotherapy and to improve the response of resistant leukemia. Adhesion of acute lymphoblastic leukemia (ALL) cells to bone marrow stromal cells triggers intracellular signals that promote cell-adhesion-mediated drug resistance (CAM-DR). Idelalisib, an U.S. Food and Drug Administration (FDA)-approved PI3K-specific inhibitor has been shown to be effective in CLL in down-regulating p-Akt and prolonging survival in combination with Rituximab; herein we explore the possibility of its use in B ALL and probe the mechanism of action. Primary B ALL in contact with OP9 stromal cells showed increased p-Akt(ser473). Idelalisib decreased p-Akt in patient samples of ALL with diverse genetic lesions. Addition of idelalisib to vincristine inhibited proliferation when compared to vincristine monotherapy in a subset of samples tested. Idelalisib inhibited ALL migration to SDF-1 in vitro and blocked homing of ALL cells to the bone marrow in vivo. This report tests PI3K inhibitors in a more diverse group of ALL than has been previously reported and is the first published report of idelalisib inhibiting homing of ALL cells to bone marrow. Our data support further pre-clinical evaluation of idelalisib for the therapy of B ALL.